PROJECT SUMMARY ? TR&D PROJECT 3 Photoacoustic Detection of Metal Fluxes at the Tissue Level Modern optical microscopic modalities offer the following optical contrasts: optical scattering, autofluorescence (intrinsic fluorescence), molecular probes (extrinsic fluorescence), and nonlinear optical effects. One key contrast, optical absorption, is inaccessible by established microscopic modalities. As a result, bioelement investigation in biological tissue mainly rely on various fluorescence probes. A lasting challenge in designing fluorescence probes is to overcome low quantum yield, where major optical energy deposited to the probes is dissipated via a non-radiative pathway as heat instead of as fluorescent emissions. Measuring nonradiative thermal generation or optical absorption could offer a new way to conduct bioelement imaging and bypass the quantum yield challenge. Imaging optical absorption quantifies ionic concentrations with high accuracy when the molar extinction coefficient is known. Imaging optical absorption permits direct quantitation of certain highly-optically absorbing ions (i.e. Fe in hemoglobin) and will stimulate the development of a new class of molecular probes that focus on high extinction coefficients only, for which the struggle to achieve high fluorescent quantum yield becomes much less critical. In this Technology Research and Development (TR&D) project we will develop a new optical absorption microscopy modality, referred to as optical Micro-Ring Resonator-Based Photoacoustic Microscopy or MRR- PAM, which measures optical absorption using ultrasound. MRR-PAM detects ultrasound waves induced by laser energy absorption and, consequently, heat generation and thermoelastic vibration. Compared with existing photoacoustic microscopy, MRR-PAM improves the ultrasound detection bandwidth and axial resolution by 10-fold and detection sensitivity by 100-fold. MRR-PAM provides a unique tool to enable tissue imaging in all the DBP themes, such as the strongly scattering brain slices, thick tissue slice or whole mouse kidney, whole zebrafish and zebrafish larvae. It will provide a new tool to quantify iron metabolism. MRR-PAM extends the imaging capabilities developed in other TR&D projects to quantify bioelement distributions and fluxes in both fixed and living tissue slices. It offers the possibility to image whole organs and, potentially, living animals. The unique MRR developed in this TR&D project can be broadly disseminated and will likely impact several other biomedical fields beyond bioelement research.